title: Sequence variant classification and reporting: recommendations for improving the interpretation of cancer susceptibility genetic test results.
abstract: Genetic testing of cancer susceptibility genes is now widely applied in clinical practice to predict risk of developing cancer. In general, sequence-based testing of germline DNA is used to determine whether an individual carries a change that is clearly likely to disrupt normal gene function. Genetic testing may detect changes that are clearly pathogenic, clearly neutral, or variants of unclear clinical significance. Such variants present a considerable challenge to the diagnostic laboratory and the receiving clinician in terms of interpretation and clear presentation of the implications of the result to the patient. There does not appear to be a consistent approach to interpreting and reporting the clinical significance of variants either among genes or among laboratories. The potential for confusion among clinicians and patients is considerable and misinterpretation may lead to inappropriate clinical consequences. In this article we review the current state of sequence-based genetic testing, describe other standardized reporting systems used in oncology, and propose a standardized classification system for application to sequence-based results for cancer predisposition genes. We suggest a system of five classes of variants based on the degree of likelihood of pathogenicity. Each class is associated with specific recommendations for clinical management of at-risk relatives that will depend on the syndrome. We propose that panels of experts on each cancer predisposition syndrome facilitate the classification scheme and designate appropriate surveillance and cancer management guidelines. The international adoption of a standardized reporting system should improve the clinical utility of sequence-based genetic tests to predict cancer risk.
authors.affiliation: Department of Pediatrics, Baylor Cancer Genetics Clinic, Baylor College of Medicine, Houston, Texas, USA. splon@bcm.edu
authors.forename: Sharon E
authors.initials: SE
authors.lastname: Plon
authors.forename: Diana M
authors.initials: DM
authors.lastname: Eccles
authors.forename: Douglas
authors.initials: D
authors.lastname: Easton
authors.forename: William D
authors.initials: WD
authors.lastname: Foulkes
authors.forename: Maurizio
authors.initials: M
authors.lastname: Genuardi
authors.forename: Marc S
authors.initials: MS
authors.lastname: Greenblatt
authors.forename: Frans B L
authors.initials: FB
authors.lastname: Hogervorst
authors.forename: Nicoline
authors.initials: N
authors.lastname: Hoogerbrugge
authors.forename: Amanda B
authors.initials: AB
authors.lastname: Spurdle
authors.forename: Sean V
authors.initials: SV
authors.lastname: Tavtigian
mesh_terms: D001483:Base Sequence; D052138:Genes, Neoplasm; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing / Q000379:methods* / Q000592:standards; D014644:Genetic Variation; D005826:Genetics, Medical / Q000592:standards*; D006801:Humans; D009386:Neoplastic Syndromes, Hereditary / Q000145:classification / Q000175:diagnosis / Q000235:genetics; D012307:Risk Factors